Menstrual Cycle-Related Symptom Variability as a Prognostic Indicator in Lymphangioleiomyomatosis

月经周期相关症状变异性作为淋巴管平滑肌瘤病的预后指标

• 批准号: 10513485
• 负责人: Nishant Gupta
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10513485
• 关键词: Aftercare; Case Study; Clinical; Cystic Neoplasm; Data; Disease Progression; Disease remission; Drug Exposure; Enrollment; Estrogens; FRAP1 gene; Female; Female of child bearing age; Future; Genes; Guidelines; Home; Hormonal; Hormonal Change; International; Intuition; Linear Models; Lung Neoplasms; Lung diseases; Luteinizing Hormone; Lymphangioleiomyomatosis; Measurable; Measures; Menstrual cycle; Monitor; Mutation; Outcome; Ovulation; Pathogenicity; Pathway interactions; Patient Outcomes Assessments; Patient Self-Report; Patients; Periodicity; Phenotype; Play; Population; Postmenopause; Pregnancy; Premenopause; Prognostic Marker; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary function tests; Quality of life; Questionnaires; Rare Diseases; Recording of previous events; Registries; Reporting; Research; Resources; Respiratory Failure; Respiratory Signs and Symptoms; Role; Safety; Series; Sirolimus; Surveys; Symptoms; Techniques; Testing; Therapeutic; Time; Training; Tuberous Sclerosis; Urine; Variant; Woman; age group; base; demographics; design; disease natural history; disorder control; efficacy study; hormone therapy; improved; innovation; novel; novel therapeutics; patient subsets; predictive marker; prognostic; prognostic indicator; pulmonary function; pulmonary function decline; pulmonary symptom; rate of change; response; symptomatic improvement; telehealth

ABSTRACT Lymphangioleiomyomatosis (LAM) is a progressive, female-predominant, cystic lung neoplasm caused by mutations in the tuberous sclerosis complex genes leading to constitutive activation of the mechanistic target of rapamycin (mTOR) pathway. In the Multicenter International LAM Efficacy of Sirolimus trial, mTOR inhibition with sirolimus was shown to stabilize lung function decline and improve quality of life in LAM patients. However, treatment with sirolimus is suppressive rather than remission inducing, does not benefit all LAM patients, and durable disease control in LAM requires long-term drug exposure. These limitations of sirolimus treatment highlight the critical need to explore novel therapies in LAM. Hormonal influences, especially estrogen, are believed to play a pathogenic role in LAM as suggested by the following observations: symptomatic LAM is restricted almost exclusively to females, LAM is exacerbated by exogenous estrogen use and pregnancy, and lung function in premenopausal women with LAM declines faster than that of postmenopausal women. Although the empirical use of hormonal agents in LAM was common in the past, the current LAM Guidelines recommend against their routine use, pending the outcome of well-done controlled trials. We submit that the key missing component in prior studies of the efficacy of hormonal agents in LAM has been the identification of the subset of patients with LAM who are most likely to benefit. We conducted a survey-based study of ~300 LAM patients and gathered information about patient demographics, clinical history including the presence of menstrual cycle associated respiratory symptom variation (MCRV), and current treatment for LAM. The key findings from this study were: 1) MCRV was reported by almost one-third of the patients with LAM, 2) treatment with sirolimus did not impact MCRV, 3) LAM patients with MCRV were less likely to report symptom improvement with sirolimus compared to patients without MCRV, and 4) patients with MCRV were more likely to report improvement after treatment with hormonal agents compared to patients without MCRV. We postulate that self-reported MCRV is associated with measurable cyclical spirometric changes, faster disease progression and suboptimal response to sirolimus in patients with LAM. In order to test our hypothesis, we will pursue the following specific aim: Determine the impact of MCRV on the rate of disease progression in patients with LAM. Successful completion of our project will enhance our understanding of the impact of hormonal changes during the menstrual cycle on lung function in LAM patients, provide the natural history of disease progression as well as response to sirolimus treatment in LAM patients with and without MCRV, and establish MCRV as a novel prognostic and predictive marker in LAM. This project is highly significant as it will establish MCRV as a unique measure that can identify the subpopulation of LAM patients who might benefit from hormonal treatment, and provide information that is both necessary and sufficient to conduct pivotal trials of hormonal agents in LAM.

摘要 淋巴管平滑肌瘤病（LAM）是一种进行性、女性为主的囊性肺肿瘤， 结节性硬化症复杂基因的突变导致的机制靶点的组成性激活， 雷帕霉素（mTOR）途径。在西罗莫司的多中心国际LAM疗效试验中， 西罗莫司可稳定LAM患者的肺功能下降并改善其生活质量。然而，在这方面， 西罗莫司治疗是抑制性的，而不是诱导缓解，并不能使所有LAM患者受益， LAM的持久疾病控制需要长期药物暴露。西罗莫司治疗的这些局限性 突出了探索LAM新疗法的迫切需要。荷尔蒙的影响，尤其是雌激素， 据信在LAM中起致病作用，如以下观察所示：症状性LAM是 LAM几乎仅限于女性，外源性雌激素的使用和妊娠会加重LAM， 绝经前LAM患者的肺功能下降速度比绝经后妇女快。虽然 在过去，激素类药物在LAM中的经验性使用很常见，目前的LAM指南建议 在良好的对照试验结果出来之前，我们认为丢失的钥匙 激素类药物在LAM中疗效的先前研究中的一个组成部分是鉴定 最有可能受益的LAM患者。我们对约300名LAM患者进行了一项基于调查的研究， 收集患者人口统计学信息、临床病史（包括月经周期的存在） 相关的呼吸道症状变异（MCRV）和当前LAM的治疗。这项研究的主要发现是， 研究结果如下：1）几乎三分之一的LAM患者报告了MCRV，2）西罗莫司治疗 不影响MCRV，3）患有MCRV的LAM患者报告西罗莫司治疗后症状改善的可能性较小 与没有MCRV的患者相比，4）MCRV患者更有可能报告在治疗后改善 与未接受MCRV治疗的患者相比，使用激素治疗。我们假设自我报告的MCRV是 与可测量的周期性肺功能变化、更快的疾病进展和次优 LAM患者对西罗莫司的反应。为了验证我们的假设，我们将继续以下内容 具体目的：确定MCRV对LAM患者疾病进展率的影响。成功 完成我们的项目将提高我们对月经期间荷尔蒙变化的影响的理解 周期对LAM患者肺功能的影响，提供疾病进展的自然史以及对 西罗莫司治疗有和无MCRV的LAM患者，并将MCRV确立为一种新的预后和 LAM中的预测标志物。该项目意义重大，因为它将确立MCRV作为一项独特的措施， 可以识别可能受益于激素治疗的LAM患者亚群，并提供 这些信息对于在LAM中进行激素药物的关键试验是必要的和充分的。